Structural Basis for HLA-DQ2-Mediated Presentation of Gluten Epitopes in Celiac Disease

Celiac disease, also known as celiac sprue, is a gluten-induced autoimmune-like disorder of the small intestine, which is strongly associated with HLA-DQ2. The structure of DQ2 complexed with an immunogenic epitope from gluten, QLQPFPQPELPY, has been determined to 2.2-Å resolution by x-ray crystallo...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-03, Vol.101 (12), p.4175-4179
Main Authors: Kim, Chu-Young, Quarsten, Hanne, Bergseng, Elin, Khosla, Chaitan, Sollid, Ludvig M., Strominger, Jack L.
Format: Article
Language:English
Subjects:
Atoms
Biological Sciences
Celiac disease
Celiac Disease - immunology
Crystallography, X-Ray
Epitopes
Epitopes - chemistry
Epitopes - immunology
Gliadin - chemistry
Gliadin - immunology
Glutens - chemistry
Glutens - immunology
HLA antigens
HLA-DQ Antigens - chemistry
HLA-DQ Antigens - immunology
Humans
Hydrogen bonds
Immunology
Ligands
Molecules
Musical register
Oxygen
Peptides
Peptides - chemistry
Peptides - immunology
Proline - chemistry
Protein Structure, Tertiary
T lymphocytes
Toxicity
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Summary:Celiac disease, also known as celiac sprue, is a gluten-induced autoimmune-like disorder of the small intestine, which is strongly associated with HLA-DQ2. The structure of DQ2 complexed with an immunogenic epitope from gluten, QLQPFPQPELPY, has been determined to 2.2-Å resolution by x-ray crystallography. The glutamate at P6, which is formed by tissue transglutaminase-catalyzed deamidation, is an important anchor residue as it participates in an extensive hydrogen-bonding network involving Lys-β71 of DQ2. The gluten peptide-DQ2 complex retains critical hydrogen bonds between the MHC and the peptide backbone despite the presence of many proline residues in the peptide that are unable to participate in amide-mediated hydrogen bonds. Positioning of proline residues such that they do not interfere with backbone hydrogen bonding results in a reduction in the number of registers available for gluten peptides to bind to MHC class II molecules and presumably impairs the likelihood of establishing favorable side-chain interactions. The HLA association in celiac disease can be explained by a superior ability of DQ2 to bind the biased repertoire of proline-rich gluten peptides that have survived gastrointestinal digestion and that have been deamidated by tissue transglutaminase. Finally, surface-exposed proline residues in the proteolytically resistant ligand were replaced with functionalized analogs, thereby providing a starting point for the design of orally active agents for blocking gluten-induced toxicity.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0306885101